Cancer is one of the most life threatening diseases in which cells in a part of the body experience out-of-control growth. According to the latest data from American Cancer Society, cancer is the 2nd leading cause of death in the USA (second only to heart disease) and claimed more than 550,000 lives in 2011. In fact, it is estimated that 50% of all men and 33% of all women living in the United States will develop some type of cancer in their lifetime. Therefore cancer constitutes a major public health burden and represents a significant cost in the United States. For decades, surgery, chemotherapy, and radiation were the established treatments for various cancers. Patients usually receive a combination of these treatments depending on the type and extent of the disease. But chemotherapy is most important treatment option when other treatments are impossible.
Topoisomerase inhibitors (also commonly referred as topoisomerase poisons) are one of the most important chemotherapy for cancer treatment. Topoisomerases are enzymes that regulate the topology of DNA by actions such as breaking, relaxing, passing, and rejoining strands of DNA in cells [Yves Pommie, Nature Reviews Cancer, 2006, 6, 789-802]. The mammalian genome encodes seven topoisomerase genes: four that encode type I topoisomerases and three that encode type II topoisomerases (TOP2alpha, TOP2beta, and SPO11). The 4 mammalian type I topoisomerase genes include nuclear topoisomerase I (generally abbreviated TOP1), the mitochondrial topoisomerase I (TOP1MT) gene and two genes that encode TOP3alpha and TOP3beta. The type I topoisomerases have been subdivided into two groups, type IA and IB, on the basis of the side of the DNA break to which the enzyme becomes covalently bound as it forms its catalytic tyrosyl-DNA cleavage intermediate, referred to as the cleavage complex. Top3 enzymes and bacterial TOP1 belong to the type IA group, as they form 5′-DNA tyrosyl adducts similar to the type II topoisomerases. TOP1 and TOP1mt belong to the type IB group, are the only known enzymes that form 3′-phosphotyrosyl bonds in eukaryotic cells. Topoisomerase has held the great interest of cancer researchers owing to the discovery that it is targeted by active anticancer drugs, notably topotecan, irinotecan, mitoxantrone, etoposide, doxorubicin, and so on.
Camptothecin, a cytotoxic quinoline alkaloid, is a natural product which inhibits the DNA enzyme topoisomerase I. Camptothecin was first isolated from the bark of the Chinese tree, camptotheca acuminata. It was discovered and developed by the US National Cancer Institute (NCI) at about the same time and by the same groups that were also working on paclitaxel (Taxol). Camptothecin binds to the topo I and DNA complex (the covalent complex) resulting in a ternary complex, and thereby stabilizing it. This prevents DNA re-ligation and therefore causes DNA damage which results in apoptosis. Camptothecin showed remarkable anticancer activity in preliminary clinical trials in the mid 1970s, but also low solubility and high adverse drug reaction. Because of these disadvantages, synthetic and medicinal chemists have synthesized many derivatives of Camptothecin to increase the benefits of the chemical, with good results. Two semisynthetic camptothecin derivatives have been approved by US FDA for cancer chemotherapy: topotecan and irinotecan. Topotecan is the water-soluble semisynthetic derivative of camptothecin and was approved to treat ovarian cancer (2nd line), cervical cancer (2nd line), and small cell lung cancer (2nd line). Irinotecan was approved as the first line treatment with 5-FU and Leucovorin for colon cancer. Some of the camptothecin derivatives are shown as following:

Although the conventional camptothecin derivatives have made a significant contribution to cancer treatment, the dose-limiting toxicities and drug resistance remain significant hurdles in the use of these drugs.
In recent years, histone deacetylases (HDAC) has emerged as an important disease target for cancer treatment [Minucci, S. et al., Nat Rev Cancer 2006, 6, 38-51]. The human HDAC enzymes have 18 isoforms grouped into Class I-IV according to their sequence homology. Class I, II and IV, commonly referred to as the classical HDACs, are comprised of 11 family members. Class III HDACs consists of 7 enzymes and they are distinct from other HDAC family members, therefore are given a unique term sirtuins. The major difference between classical HDACs and sirtuins reside on their catalytic mechanisms. Classical HDAC contains a catalytic pocket with a Zn2+ ion at its base that can be inhibited by Zn2+ chelating compound. In contrary, all sirtuins are using NAD+ as cofactor in their deacetylase action.
The inhibition of HDAC enzyme leads to histone acetylation which is associated with the remodelling of chromatin and plays a key role in the epigenetic regulation of gene expression. In addition, HDAC inhibitors have been shown to evoke the acetylation of many important non-histone proteins such as HSP90, alpha-tubulin, Ku-70, Bcl-6, importin, cortactin, p53, STAT1, E2F1, GATA-1 and NF-kB, which can alter many important signaling networks related to cancer treatment. The underlying mechanism of action of HDAC inhibitors includes the differentiation, cell cycle arrest, inhibition of DNA repair, induction of apoptosis, upregulation of tumor suppressors, down regulation of growth factors, oxidative stress and autophagy. In the last decade, a large number of structurally diverse HDAC inhibitors have been identified and at least 12 HDAC inhibitors are currently in human clinical trials for cancer treatments, including short-chain fatty acid (valproic acid), hydroxamates (SAHA, LBH589, PXD101, JNJ-26481585, ITF2357, CUDC-101), cyclic tetrapeptides (FK-228), benzamide (MS-275), and several other compounds (CHR-3996, 4SC-201, SB939). Among them, SAHA and FK-228 has been approved by the US FDA for the treatment of advanced cutaneous T-cell lymphoma.
Certain HDAC inhibitors and camptothecin derivatives (such as Topotecan, Irinotecan) synergistically block cell proliferation when used in combination (Bruzzese et al, Mol Cancer Ther. 2009 November; 8(11):3075-87; Sarcar B, et al, J. Neurooncol. 2010, September; 99(2):201-7; Sato A, et al. Oncol Res. 2011; 19(5):217-23).